Racial disparities in the association between diabetes mellitus-associated polymorphic locus rs4430796 of the HNF1ß gene and prostate cancer: a systematic review and meta-analysis.

Polymorphism 17q12 rs4430796 within HNF1ß is a genetic variant associated with both diabetes mellitus and prostate cancer, but findings on the correlations of rs4430796 with prostate cancer risk specifically are not in agreement, especially among diverse populations. To shed some light on the contradictory findings, therefore, we carried out a meta-analysis by pooling the odds ratios (ORs) with corresponding 95% confidence intervals (CIs) of all currently available case-control studies located within PubMed and Embase databases up to December 2012. A total of 16 studies comprising 30 datasets that collectively involved 25,535 prostate cancer patients and 25,726 controls were ultimately included in this analysis. The meta-analysis of all the studies revealed that the rs4430796 polymorphism was significantly associated with an increased risk of prostate cancer in all contrast models (ORA vs G = 1.25, 95%CI = 1.21-1.30, POR < 0.001; ORAA vs GG = 1.53, 95%CI = 1.45-1.62, POR < 0.001; ORAG vs GG = 1.24, 95%CI = 1.16-1.34, POR < 0.001; ORAA vs AG+GG = 1.36, 95%CI = 1.30-1.42, POR < 0.001; ORAA+AG vs GG = 1.37, 95%CI = 1.30-1.44, POR < 0.001). After subgroup analyses stratified by ethnicity, however, the rs4430796 polymorphism was significantly associated with prostate cancer in both Caucasians and Asians but not in African-Americans. In conclusion, our meta-analysis identified a significant association between the 17q12 rs4430796 polymorphism and prostate cancer risk, although the degree of this association and frequency of the causative allele varied among men of different races.

Mapping the interactions between Escherichia coli TolQ transmembrane segments.

The tolQRAB-pal operon is conserved in Gram-negative genomes. The TolQRA proteins of Escherichia coli form an inner membrane complex in which TolQR uses the proton-motive force to regulate TolA conformation and the in vivo interaction of TolA C-terminal region with the outer membrane Pal lipoprotein. The stoichiometry of the TolQ, TolR, and TolA has been estimated and suggests that 4-6 TolQ molecules are associated in the complex, thus involving interactions between the transmembrane helices (TMHs) of TolQ, TolR, and TolA. It has been proposed that an ion channel forms at the interface between two TolQ and one TolR TMHs involving the TolR-Asp(23), TolQ-Thr(145), and TolQ-Thr(178) residues. To define the organization of the three TMHs of TolQ, we constructed epitope-tagged versions of TolQ. Immunodetection of in vivo and in vitro chemically cross-linked TolQ proteins showed that TolQ exists as multimers in the complex. To understand how TolQ multimerizes, we initiated a cysteine-scanning study. Results of single and tandem cysteine substitution suggest a dynamic model of helix interactions in which the hairpin formed by the two last TMHs of TolQ change conformation, whereas the first TMH of TolQ forms intramolecular interactions.

Channel domain of colicin A modifies the dimeric organization of its immunity protein.

Proteins conferring immunity against pore-forming colicins are localized in the Escherichia coli inner membrane. Their protective effects are mediated by direct interaction with the C-terminal domain of their cognate colicins. Cai, the immunity protein protecting E. coli against colicin A, contains four cysteine residues. We report cysteine cross-linking experiments showing that Cai forms homodimers. Cai contains four transmembrane segments (TMSs), and dimerization occurs via the third TMS. Furthermore, we observe the formation of intramolecular disulfide bonds that connect TMS2 with either TMS1 or TMS3. Co-expression of Cai with its target, the colicin A pore-forming domain (pfColA), in the inner membrane prevents the formation of intermolecular and intramolecular disulfide bonds, indicating that pfColA interacts with the dimer of Cai and modifies its conformation. Finally, we show that when Cai is locked by disulfide bonds, it is no longer able to protect cells against exogenous added colicin A.

Mapping the interactions between escherichia coli tol subunits: rotation of the TolR transmembrane helix.

The TolQRA proteins of Escherichia coli form an inner membrane complex involved in the maintenance of the outer membrane stability and in the late stages of cell division. The TolQR complex uses the proton motive force to regulate TolA conformation and its interaction with the outer membrane Pal lipoprotein. It has been proposed that an ion channel forms at the TolQR transmembrane helix (TMH) interface. This complex assembles with a minimal TolQ:TolR ratio of 4-6:2 and therefore involves 14-20 TMHs. To define the organization of the transmembrane helices in the membrane within the TolQR complex, we initiated a cysteine scanning study. In this study, we report results for the systematic replacement of each residue of the TolR TMH. Phenotypic analyses first showed that most of the mutants are functional. Three mutants, TolR L22C, D23C, and V24C, were shown to affect TolQR functioning. Disulfide bond complex formation further showed that two TolR anchors are close enough to interact. Two substitutions, L22C and V24C, form high level of dimers, suggesting that the TolR helix rotates as molecular gears between these two positions and that disulfide bond formation between these residues blocked the rotary motion. Mutations of critical residues located within the TolQ TMH2 and TMH3 and the TolR TMH and proposed to form the ion pathway prevent rotation between these two residues. TolR anchors may form molecular gears that oscillate in response to proton motive force to regulate channel activity.

[Study on the subclinical infection of the recipients of measles vaccine].

Through observation to subclinical infection of the 71 children who had been inoculated against measles 12 years ago and then exposed to natural measles from three classes at a primary school, we have noticed: (1) Subclinical infection did exist among the crowd who were inoculation against measles; The rate of subclinical infection of the three classes was between 18.5%-75.0%, with an average of 45.1%. (2) The level of the HI Ab titer was between 1:2-1:16. The peak level was between 1:2 and/or 1:4. So the rate of subclinical infection who had been inoculation against measles but later exposed to natural measles would depend on the proportion of those whose titer of HI Ab was 1:2-1:4 in the crowd. (3) The epidemiological significance of subclinical measles infection lies in that it can actively keep and consolidate the level of immunity to certain extent in a crowd who had been inoculation against measles.

Duration of immunity following immunization with live measles vaccine: 15 years of observation in Zhejiang Province, China.

The duration of immunity following measles vaccination of 2882 immunized children has been investigated in a closed region of China for 15 years. A total of 1002 of the children were treated as primary immunization subjects, and 1547 as reimmunization subjects. These two cohorts were not in contact with known wild measles virus over the whole observation period, and the results obtained probably reflected the antibody responses to measles vaccine alone. The remaining 333 vaccinees came into contact with wild measles virus, and this permitted evaluation of the protective effect of the measles vaccines tested: 4 children experienced very mild clinical measles, and 329 experienced subclinical infection, including 12 who had had undetectable haemagglutination-inhibition antibodies for 9-10 years. These results indicate that the immunity induced by successful primary immunization may persist for at least 15 years. Within this period, a second dose of vaccine only induces low antibody responses which decrease rapidly to their original levels. This provides strong evidence that the immunity produced by primary immunization is long-lasting. However, there were some indications that reimmunization might produce better effects if live attenuated measles virus were used with a longer interval between doses.

PIP: The duration of immunity following measles vaccination of 2882 immunized children has been investigated in a closed region of China for 15 years. A total of 1002 children were treated as primary immunization subjects, and 1547 as reimmunization subjects. These 2 cohorts had no contact with known wild measles virus over the entire observation period, and the results obtained probably reflected the antibody responses to measles vaccine alone. The remaining 333 vaccines came into contact with wild measles virus, and this allowed for the evaluation of the protective effect of the measles vaccines tested. 4 children experienced very mild clinical measles and 329 experienced subclinical infection, including 12 who had had undetectable hemagglutination-inhibition antibodies for 9-10 years. These results indicate that the immunity induced by successful primary immunization may persist for at least 15 years. Within this period of time, a 2nd dose of vaccine only induces low antibody responses which decreases rapidly to their original levels. This demonstrates strong evidence that the immunity produced by primary immunization is long lasting. However, there were indications that reimmunization might produce better results if live attenuated measles virus were used with a longer interval between doses.